Kaposi's sarcoma associate herpesvirus (KSHV) is a tumorigenic gammaherpesvirus associated with AIDS-related malignancies, including Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. Herpesviruses exist in two states, a quiescent state of latency and a lytic virus-producing state characterized by expression from the entire viral genome. Reactivation of KSHV from latency results in the expression of lytic genes that potentially contribute to transformation and disease progression (e.g. viral cytokines). Therefore, understanding the mechanism controlling KSHV reactivation is an important public health issue. A KSHV transcriptional activator, Rta, is sufficient and necessary for driving viral reactivation from latency and activating lytic gene expression. The goal of this research proposal is to elucidate the direct viral targets and the cellular targets of Rta. A novel protein delivery method using an HIV-1 Tat peptide fused to Rta will be combined with DNA microarray analysis. Tat-Rta will be exogenously delivered to latently-infected cells in the presence of a protein synthesis inhibitor and gene expression will be screened to determine the direct targets of Rta. Analyzing the viral and cellular gene expression patterns induced by KSHV Rta will provide insight into the molecular interactions regulating the life cycle and pathogenesis of KSHV, and may aid in the development of novel therapeutic regimes for KSHV-associated malignancies.